Hepatitis B
Table of Contents
Hepatitis A · Hepatitis B · Hepatitis
C · Hepatitis
of Unknown Etiology
Hepatitis Main Page
What Is Hepatitis B?
Hepatitis B is a virus that causes acute and chronic hepatitis. While most
persons recover from hepatitis B infection, 90% of infants, 30% of children,
and 10% of adults become chronically infected. Persons who are chronically
infected with hepatitis B are at an increased risk for the development of
cirrhosis and liver cancer. An effective vaccine to prevent hepatitis B has
been licensed since 1981. This vaccine is currently recommended for all children
and adolescents.
Hepatitis B virus (HBV) infection is a serious public health problem in many areas of the world. In some regions of Asia, Africa, and the South Pacific the prevalence of hepatitis B surface antigen (HBsAg) exceeds 10%. In many of these areas, HBV-associated hepatocellular carcinoma (HCC) is a leading cause of death from cancer.
In 1972, AIP and the Alaska Area Native Health Service (AANHS) began conducting epidemiologic surveys of the prevalence, incidence, transmission, and sequelae of HBV infection among the Eskimos living in southwest Alaska. The prevalence of HBsAg was 6.4%, with considerable village-to-village variation. The incidence of new HBV infection was high, especially in children aged < 2 years and in household contacts of HBsAg-positive persons. Transmission was highest between children positive for hepatitis B e antigen (HBeAg) and those negative for all HBV seromarkers. Infected children had a significantly higher risk of becoming chronic carriers of HBsAg than did adults. Although 4.5% of prenatal women were HBsAg positive, only 24% of these were also HBeAg positive, indicating that perinatal transmission played a much smaller role than child-to-child transmission in the spread of infection in this population. In adults, HBV infection was probably acquired both from HBeAg-positive children and through sexual contact. HBV infection seemed to spread first among household contacts, then to other villagers, and finally, from village to village.
The rate of HBsAg-associated sequelae among Alaskan Natives was also high. The annual incidence of HBsAg-positive necrotizing vasculitis was 15 cases per 100,000 population. The annual incidence of HCC in Alaskan Eskimo males was 11.2 cases per 100,000, five times that of white males in the United States. Studies of HBsAg-positive HCC patients have shown that serum alpha-fetoprotein (AFP) levels were raised as early as 2 years before clinical presentation of tumor, and that twice yearly AFP screening of HBsAg carriers could detect HCC at a earlier and potentially curable stage. End stage liver disease is also a complication of chronic HBV infection. A study in this population has demonstrated that most persons with chronic HBV go from an active to an inactive stage without antiviral therapy. Once this occurs, the risk of end stage liver disease decreases dramatically but the risk of HCC remains. While a few antiviral drugs are available and more are in development, studies show that these drugs do not eradicate HBV but increase the chances over a short interval of converting a person from the active to inactive stage of the disease. However, for those who don't rapidly convert, stopping the antiviral usually results in the recurrence of active disease and continuing the antiviral leads to eventually resistance to the drug in most cases. Recently a study in this population has been initiated to identify factors associated with progression of liver disease so that early intervention with antiviral drugs can be implemented.
In 1981, a hepatitis B vaccine demonstration project conducted in the Y-K Delta among 1,600 Alaska Natives showed that in 95% of the study participants, antibody to HBsAg (Anti-HBs >10 standard ratio units by radioimmunoassay) developed after three doses of hepatitis B vaccine. These people have been followed up for 15 years to determine the long-term protection from this vaccine. In addition, a large group of infants who received the hepatitis B vaccine are being followed up to determine long-term protection in children.
Perspective
Infection with the hepatitis B virus (HBV) is a serious health problem in many parts of the world. In some populations over 10% of the population is positive for (HBsAg), which indicates active infection. Hepatitis B is a serious health concern in the United States as well. Annually 10,000 new cases of hepatitis B reported in the U.S. [CDC 1995], with an estimated one to two million carriers of HBV. In the United States the prevalence of serologic markers for present or past hepatitis B infection is approximately 5%. The rate for Native Americans in the contiguous United States is lower, with comparative rates for the Sioux and Navajo, for example, of 1-2% [Ahtone & Kubershki 1982, Shaw et al. 1993].
In the Alaska Native population, however, the prevalence of hepatitis B has been very high. The first clue appeared in 1972 when 98% of 50 acute cases of hepatitis in western Alaska were all found to be HBsAg positive by the recently available antigen test [McMahon et al. 1981]. This prompted a serologic prevalence study in two Alaska Native villages. Fourteen percent were HBsAg positive and 41% had antibody to hepatitis B (anti-HBs) [Barrett et al. 1977]. Studies were broadened in the 1970s to cover the larger Yukon-Kuskokwim (Y-K) Delta Eskimo population of southwest Alaska. Twenty-four percent were seropositive (HBsAg and anti-HBs) for hepatitis B [Schreeder et al. 1983]. In 1983 an even broader serum screening for markers was conducted in 53,000 Alaska Natives, or 68% of the entire Alaska Native population. The total positivity (HBsAg and anti-HBs) was 14% of the population with considerable variation by region. The highest total hepatitis B seroprevalence rates were in the Yupik Eskimo regions of Bristol Bay and Y-K Delta, which were the highest in the nation.
Hepatitis B infection steadily spread in Alaska Native villages. The prevalence of HBsAg increased 79% between 1972 and 1982 in the Y-K Delta villages previously surveyed, and the prevalence of any hepatitis B marker increased 63% [McMahon & Wainwright 1990]. When a plasma-derived hepatitis vaccine became available in 1981, a vaccine demonstration project was instituted in the hyperendemic western Alaska region. Nearly 4000 Eskimo residents of 17 villages were screened for HBV markers and 1630 susceptible persons were vaccinated. After three doses of hepatitis B vaccine, 97% developed detectable anti-HBs, proving that hepatitis B vaccine could be successfully administered to persons living in remote villages where difficult travel and extreme cold could become obstacles to effective immunization [Heyward et al. 1985a]. After 10 years, the annual incidence of hepatitis B infection in this group declined from 50 cases per 1000 population to less than one per 1000 [Wainwright et al. 1997]. Only 1% became core antibody (anti-HBc) positive, indicating hepatitis B infection, but none of these persons who acquired anti-HBc were symptomatic or remained HBsAg positive.
Hepatitis B infection is particularly important in children. In the 1983 serosurvey, by 10 years of age 17-19% of the children in Bristol Bay and the Y-K Delta were seropositive (HBsAg and anti-HBs) [McMahon et al. 1993]. In the hyperendemic villages, the hepatitis B virus spread rapidly from child to child, especially under the age of 2 years. HBeAg, associated with infectivity and high levels of viral replication, was found in >95% of HBsAg-positive children under 5 years of age [Alward et al. 1985] and tended to decrease with age [McMahon et al. 1993].
Transmission of hepatitis B virus generally occurs most commonly and efficiently through percutaneous, sexual, and perinatal exposures. However, in Alaska, compared to other parts of the world, the perinatal route plays a less important role. Among the Alaska Natives who become HBsAg carriers, the majority are infected after birth but before the fifth birthday [McMahon et al. 1985, Estroff et al. 1985]. Child-to-child transmission is the dominant role in the spread of hepatitis B virus. Common vectors are important in transmission in children noted by the HBsAg found in impetiginous lesions and in gingival washings of carriers as well as on the walls of homes and on the school lunchroom tables [McMahon & Wainwright 1990].
Those Alaska Native children infected at less than age 5 years had a nearly 30% risk of becoming chronically infected compared to a rate one-third that for persons infected at later then 10 years of age [McMahon et al. 1985]. There was an inverse relationship between age at infection and the development of the chronic carrier state, but with increased age at the time of infection there was increased likelihood of clinically apparent acute hepatitis B [McMahon et al. 1985]. Only 10% of persons infected under 5 years of age developed clinical hepatitis versus 33% of those over 30 years of age [McMahon et al. 1985]. Not only were the children under 5 years the primary reservoir for infection, but they also were more likely to suffer the long-term sequelae of the infection. Some of these sequelae are necrotizing vasculitis, hepatocellular carcinoma, chronic active hepatitis, and cirrhosis of the liver. The annual incidence of hepatitis B-associated necrotizing arteritis was 15 per 100,000 population, the highest reported in the world [McMahon et al. 1989]. The incidence of chronic active hepatitis, or its secondary cirrhosis, in hepatitis B carriers was 193 and 107 per 100,000, respectively, in Alaska Native men and 158 and 95 per 100,000 in women [McMahon et al. 1990a].
The majority of HCC cases are associated with hepatitis B virus infection. In a prospective study of 1400 Alaska Native HBsAg positive carriers, the relative risk of developing HCC was 148 compared to the general population. The HCC incidence in Alaska Native men was 2.3/1000 and in women was 1.2/1000 [McMahon et al. Ann Intern Med 2001]. Although the carcinoma develops many years after chronic HBsAg carriage is acquired, the Alaska Native carriers under the age of 20 years had a high incidence of HCC [McMahon et al. 1990a]. In the 1970s the HCC case-fatality rate in Alaska Natives was 100% with a mean survival of less than 3 months following diagnosis [Heyward et al. 1981]. Then an important finding was made in Alaska Native patients: serum alpha-fetoprotein (AFP), an embryonic protein, could be elevated up to two years prior to the clinical presentation of hepatocellular carcinoma [Heyward et al. 1982]. Now twice yearly AFP screening of Alaska Native HBsAg carriers can detect HCC at a earlier and potentially curable stage [Heyward et al. 1985b]. Significant 5 and 10 year survival benefit has been demonstrated in screened persons compared with historical controls following inception of AFP screening [McMahon et al, Hepatology 2000].
In 1982, a statewide program was instituted to immunize all serosusceptible Alaska Natives and all newborn Alaska Natives, and to administer hepatitis B immune globulin (HBIG) to those born of HBsAg-positive mothers [McMahon et al. 1990b]. Between 1982 and 1987, over 52,000 Alaska Natives were screened for hepatitis B markers and over 43,000 susceptibles were identified and vaccinated. In the Y-K Delta, where surveillance was established prior to the hepatitis B control program and where 90% of susceptibles were vaccinated, the incidence of acute symptomatic hepatitis B cases decreased from 215 cases per 100,000 population to 6 per 100,000 within 5 years and subsequently has fallen to <1% (see figure). The proportion of infants born to HBsAg-carrier mothers who became chronically infected fell from 40% to 1% [McMahon & Wainwright 1990]. Since an earlier study showed that only 14% of persons who acquired HBV infection had clinically apparent hepatitis, the actual incidence of HBV infection before immunization was probably greater than 1500 per 100,000. This demonstrated that community-based mass immunization can effectively reduce acute symptomatic HBV infection in at least 90% of susceptible persons in a hyperendemic population [McMahon & Wainwright 1990].
Since 1985, hepatitis B has been a routine infant immunization for Alaska Natives. In addition, since 1987, hepatitis B vaccine has continued to be offered to all Alaska Natives who are found to be seronegative on screening. Over 1400 persons who are chronically infected with hepatitis B (HBsAg carriers) are followed with semi-annual screening for AFP since 1982. Thirty-four patients with HCC have been identified; 26 of them had tumors small enough for surgical removal.
Control Program
- In, March 1983, a statewide hepatitis B control program was instituted with the cooperative efforts of the AANHS, AIP, and the State of Alaska Division of Public Health. The objective was to vaccinate all serosusceptible Alaska Natives in order to eliminate new HBV infection. An ongoing maintenance phase includes universal vaccination of all newborn Alaska Natives and, in addition, administration of HBIG to those born of HBsAg-positive mothers. A serosurvey in Bristol Bay in 1994 demonstrated that no children < 10 years of age were HBsAg-positive, whereas the HBsAg-positive rate in children > years of age was >10%, thus demonstrating the effect of infant immunization.
- Serologic testing to determine HBV status prior to immunization allowed all HBV carriers to be identified. These patients are being carefully followed and tested for AFP and liver aminotransferase levels, in addition to HBV markers. Testing for AFP tumor marker prospectively allows HCC to be detected at an early, resectable stage. Testing for aminotransferase levels can identify persons with active liver disease who might benefit from anti-viral therapy.
Accomplishments
- Continued active follow-up of over 300 Alaska Native children vaccinated in infancy who have their responses to the primary series documented to determine duration of protection provided by hepatitis B vaccines.
- Completed the evaluation of differing booster doses of hepatitis B vaccine in previously immunized adult hospital employees in order to determine optimum dosage for boosting.
- Completed the enrollment of 300 children in a study to boost those who retained less than "protective" antibody to hepatitis B at 5 and 9 years. Completed a second "primary" vaccine series on those who failed to respond to the initial booster dose. While the preliminary findings suggest that 87% of the 5 year olds and 72% of the 9 year-olds are protected, the study raises concerns about long-term protection of this vaccine in those immunized starting at birth. This study is significant because it is the longest duration of documented outcome of low-risk infants vaccinated at birth and has implications for establishing the time of a booster dose in childhood.
- Conducted follow-up in 17 villages in western Alaska, where over 1600 individuals had received hepatitis vaccine 15 years earlier. The significance of this project is twofold. First, it was demonstrated that a remote population could be effectively vaccinated, which led the way for the cooperative statewide hepatitis B control program, which has significantly decreased the incidence of acute hepatitis B and will likely decrease the long-term sequelae. The strategy used in the control program has been integrated in control programs in other countries. Secondly, this project is significant because it demonstrates the long-term effectiveness of a vaccination program in a high-risk population. Information gathered in this program is of national and international interest. The information gathered on the long-term efficacy and safety of the hepatitis B vaccine is being used to develop policy for revaccination schedules.
- Supported the continued Indian Health Service (IHS) biannual screening of hepatitis carriers for alpha- fetoprotein (AFP) in order to detect hepatocellular carcinoma while in an early and potentially curable stage. This program developed in Alaska is a model for HCC control in other parts of the United States and in other countries.
- In conjunction with the Hepatitis Division, NCID, CDC completed analysis of a study to determine the prevalence of hepatitis A, B, C, D, and E in six villages in southwest Alaska where routine hepatitis B vaccination was implemented 10 years previously. The prevalence of HBsAg was zero in children 2 to 10 years of age compared to 15% of age-matched controls tested in 1983. This demonstrates that similar results could be accomplished in other endemic areas utilizing childhood vaccination programs.
- Supported a study conducted by ANMC and Hepatitis Division, NCID, CDC to give a booster dose to 200 children ages 5-7 and 200 adolescents who received initial hepatitis B immunization course starting at birth, to determine if immune memory is intact and if booster doses would be needed at these ages.
- Participated with the Alaska Native Tribal Health Consortium (ANTHC) in a NIH supported study to test hepatitis B carriers every six months to determine clinical, serologic and biologic factors associated with the development of HBV sequelae.
- Assisted ANMC in the development of a molecular biology laboratory that can be used for clinical and research purposes.
Future Plans
- To continue the long term follow-up of over 300 infants vaccinated with hepatitis B vaccine in infancy.
- To analyze serum samples from the 15-year follow-up on 1,000 Alaska Native vaccine recipients in western Alaska.
- To develop a study to test Alaska Native vaccine recipients in western Alaska 22 years after initial immunization and determine the response to a booster dose in those who have no measurable protective antibody.
- To continue an assessment of immunity and response to boosters and to further characterize the persistence of protection provided by hepatitis B vaccine when administered in infancy.
- To continue to analyze the results of the AFP screening program.
- To continue to participate in the study to test hepatitis B carriers every six months to determine clinical, serologic and biologic factors associated with the development of HBV sequelae.
- To evaluate the impact integration of the hepatitis B control program into the fabric of the health care system in Alaska with regards to rates of new infection and subsequent sequelae.
References
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